The world of powered two-wheelers has changed dramatically in recent decades, along with a steady increase in the number and diversity of the fleet and uses. This evolution has led to some benefits in terms of mobility, but also some drawbacks in terms of safety. The problems involved are neither simple nor monolithic and there is a lack of knowledge about their different facets and backgrounds that require research work both in terms of risk exposure, accidents factors and impact severity. This special issue of Accident Analysis and Prevention regroups 30 papers devoted to an improvement in this knowledge, exploring the different aspects involved in the safety of powered two-wheelers by complementary methods.